Schizophrenia is the most common chronic psychotic disorder of humans, affecting approximately one percent of the population worldwide (Eaton, Epidemiol Rev, 7:105, 1985). The mean lifetime risk of schizophrenia has been estimated at one percent (Eaton, supra, 985). As the onset of disease usually occurs early in life, and results in serious chronic impairment of cognition, behavior, and emotional state, schizophrenia is a major social problem in terms of cost, lost potential and productivity, and family stress. Furthermore, estimates indicate that the mortality of schizophrenic patients is twice that of the general population (Tsuang et al., Arch Gen Psychiat, 36:1295, 1979). The medical care of schizophrenic patients also presents a significant challenge, as the patients are often unable to provide an accurate medical history, and have difficulty complying with medical treatment.
The essential features of schizophrenia are the presence of psychotic symptoms during some phase of the illness, a chronic course, and deterioration in function. However, no combination of signs or symptoms is truly pathognomic of the disease. The DSM-IV criteria for schizophrenia (See, Hyman, “Schizophrenia,” in Dale and Federman (eds.), Scientific American Medicine, New York, N.Y., 13 VII:1-5, 1994), requires a duration of at least six months, and a deterioration in function. Psychotic symptoms typically exhibited by schizophrenia patients include disturbances in perception, abnormalities in thought content, and abnormalities in the form of thought. Perceptual disturbances typically consist of hallucinations and illusions. The course of schizophrenia is variable, although it is generally characterized by periods with exacerbation of psychotic symptoms, followed by periods of remission. Over a period of years, social and cognitive function usually deteriorates. Suicide attempts and depression are common. As measured by frequency and severity of relapses, continuing symptoms, and overall functioning, approximately 80% of schizophrenics have a poor outcome (Breier et al., Arch Gen Psychiat, 48:239, 1991).
Although family, twin, and adoption studies indicate that schizophrenia has a significant genetic component, these studies also show that the inheritance of schizophrenia is complex, involving an uncertain mode of transmission, incomplete penetrance, and probable genetic heterogeneity (Risch, Genet Epidemiol, 7:3, 1990; and Tsuang, Brit J Psychiat, 163:299, 1993). Linkage studies using schizophrenia and related psychiatric cases as phenotypes have found possible loci for schizophrenia at various chromosomal sites in subsets of families (Pulver et al., Am J Med Genet, 54:44, 1994; Coon et al., Am J Med Genet, 54:12, 1994; Wang et al., Nature Genet, 10:41, 1995; and Silverman et al., Am J Med Genet, 67:162, 1996). However, the findings do not account completely for the inheritance of schizophrenia, nor do they delineate which aspects of this multifactorial illness might be influenced by a specific locus.
A variety of psychiatric disorders may mimic schizophrenia and the symptoms of many disorders are similar. Thus, diagnosis has been based on the course of illness (for example, acute onset and episodic course in mania, compared with an insidious onset and chronic course in schizophrenia). In addition to schizophrenia, psychotic symptoms may also occur as a result of metabolic disturbances, structural brain lesions, other medical conditions, or drug toxicity. Thus, the differential diagnosis of schizophrenia must take into consideration such medical conditions as central nervous system neoplasm, hyperviscosity syndromes (i.e., due to hematologic malignancy), paraneoplastic syndromes, anoxia and postanoxic encephalopathy, hypertensive encephalopathy, AIDS encephalopathy, encephalitis, meningitis, brain abscess, Lyme disease, neurosyphilis, acute intermittent porphyria, Addison's disease, Cushing's disease, hepatic encephalopathy, hypocalcemia, hypercalcemia, hypoglycemia, hypothyroidism, hyperthyroidism, Alzheimer's disease, complex partial seizures, Huntington's disease, multiple sclerosis, stroke, Wilson's disease, folic acid deficiency, pellagra, vitamin B12 deficiency, and lupus cerebritis. Some drugs, such as alcohol, high-dose cocaine, high-dose amphetamines, marijuana, phencyclidine (PCP), hallucinogens, sedative-hypnotics, meperidine, non-steroidal anti-inflammatory drugs, pentazocine and other opiate mixed agonist-antagonists, anti-tuberculosis drugs (e.g., cycloserine, isoniazid, rifampin), other antimicrobials, anticholinergic anti-parkinsonians, anti-histamines (e.g., diphenhydramine), atropine and derivatives, cyclic antidepressants, low-potency antipsychotic drugs (e.g., thioridazine and clozapine), meclizine, scopolamine, anti-arrhythmic (e.g., amiodarone, digitalis, and procainamide), captopril, amantadine, D2 dopamine receptor antagonists (e.g., bromocriptine, and pergolide), levodopa, estrogens, testosterone, glucocorticoids and adrenocorticotropic hormone (ACTH), thyroid replacement overdose, cimetidine, ranitidine, dextroamphetamine, methylphenidate, and over-the-counter decongestants (e.g., pseudoephedrine), diet pills, and pep pills, are commonly associated with psychotic symptoms.
Treatment of schizophrenic patients usually involves the use of anti-psychotic drugs (e.g., haloperidol, haloperidol-like drugs, and a typical neuroleptics such as clozapine), maintenance of a safe, predictable environment, and supportive psychotherapy to improve social and coping skills of patients. Stress reduction also appears to prevent relapses. While these drugs are useful in treating the symptoms of schizophrenia, there are also problems associated with their use. For example, the use of clozapine is complicated by the idiosyncratic occurrence of agranulocytosis, necessitating weekly monitoring of the white blood cell counts of patients taking this drug (See, Hyman, supra, 1994).
Despite advances in treatment and diagnostic methods, there remains a need for methods to diagnose and treat schizophrenic patients. Indeed, methods to diagnose and screen large populations for genetic component(s) associated with schizophrenia, as well as other psychoses are needed in order to provide reliable diagnoses that are not dependent upon the multifactorial criteria presently in use. Improved methods of treatment are also needed, including drugs and other therapeutics that do not have the side effects and other undesirable properties associated with the currently used drugs.